Abstract
Breast cancer resistance protein (BCRP) is a recently identified ATP-binding cassette transporter, important in drug disposition and in the development of multidrug resistance in cancer. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be human BCRP inhibitors. The objective of the present study was to evaluate the potential for in vivo pharmacokinetic interactions by comparing the pharmacokinetics of topotecan (a model BCRP substrate) after oral administration of 2 mg/kg topotecan with and without different doses of the flavonoids chrysin or 7,8-benzoflavone (BF) in rats and mdr1a/1b (–/–) mice. Coadministration of 50 mg/kg GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9, 10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] with 2 mg/kg topotecan significantly increased the area under the plasma concentration-time curve and bioavailability of topotecan by more than 4-fold in these animals, indicating the importance of BCRP in the bioavailability and disposition of topotecan in rats. Chrysin (50 μM) and BF (5 μM) significantly inhibited the BCRP-mediated transport of topotecan in BCRP-overexpressing MCF-7 MX100 cells (MCF-7 cells selected with mitoxantrone) to a level comparable to that observed with 10 μM fumitremorgin C (a potent BCRP inhibitor). However, neither chrysin nor BF significantly altered topotecan pharmacokinetics in rats or in mdr1a/1b (–/–) mice after oral coadministration of doses up to 50 mg/kg. The reason(s) for this lack of in vitro-in vivo association may be the lack of potent inhibition activity of the flavonoids against mouse or rat BCRP, as evidenced by our observation that these flavonoids have only weak, if any, inhibition activity against mouse Bcrp1-mediated transport of topotecan in MDCK-Bcrp1 cells.
Footnotes
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Financial support for this study was provided by grants from the Susan G. Komen Breast Cancer Foundation and Pfizer Global Research and Development. S.Z. was the recipient of a graduate fellowship from Pfizer Global Research and Development.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002501.
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ABBREVIATIONS: BCRP, breast cancer resistance protein; BF, 7,8-benzoflavone; FTC, fumitremorgin C; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; MCF-7 MX100, MCF-7 cells selected with mitoxantrone; MRP1, multidrug resistance-associated protein 1; PBS, phosphate-buffered saline; HBSS, Hanks' buffered salt solution; PSC833, valspodar; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; SD, Sprague-Dawley; AP, apical; BL, basolateral; AUC, area under the plasma concentration-time curve.
- Received September 26, 2004.
- Accepted December 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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